Dexamethasone inhibits lipopolysaccharide‐induced hydrogen sulphide biosynthesis in intact cells and in an animal model of endotoxic shock

摘要

Dexamethasone (1 mg/kg, i.p.) administered either 1 hr before or 1 hr after E. coli lipopolysaccharide (LPS, 4 mg/kg, i.p.) in conscious rats inhibited the subsequent (4 hrs) rise in plasma cytokine (interleukin [IL]‐1β, tumour necrosis factor [TNF]‐α), nitrateitrite (NO×), soluble intercellular adhesion molecule‐1 (sICAM‐1) concentration and lung/liver myeloperoxidase activity indicative of an anti‐inflammatory effect. Dexamethasone also reduced the LPS‐evoked rise in plasma hydrogen sulphide (H2S) concentration, liver H2S synthesizing activity and expression of cystathionine γ lyase (CSE) and inducible nitric oxide synthase (iNOS). Mifepristone (RU‐486) inhibited these effects. Dexamethasone (1–10 μM) reduced the LPS‐evoked release of IL‐1β, TNF‐α and L‐selectin, decreased expression of CSE and iNOS and diminished nuclear factor κB (NF‐κB)‐DNA binding in isolated rat neutrophils. In contrast, NaHS (100 μM) increased L‐selectin release from rat neutrophils. Dexamethasone also reduced LPS‐induced up‐regulation of CSE in foetal liver cells. 6‐amino‐4‐(4‐phenoxyphenylethylamino) quinazoline (QNZ, 10 nM), a selective inhibitor of transcription via the NF‐κB pathway, abolished LPS‐induced up‐regulation of CSE expression. We propose that inhibition of CSE expression and reduction in formation of the pro‐inflammatory component of H2S activity contributes to the anti‐inflammatory effect of dexamethasone in endotoxic shock. Whether H2S plays a part in the anti‐inflammatory effect of this steroid in other forms of inflammation such as arthritis or asthma warrants further study.